Essential Oils Modulate Gene Expression and Ochratoxin A Production in Aspergillus carbonarius.
Ochratoxin A (OTA) is a mycotoxin, mainly produced on grapes by Aspergillus carbonarius, that causes massive health problems for humans. This study aims to reduce the occurrence of OTA by using the ten following essential oils (E.Os): fennel, cardamom, anise, chamomile, celery, cinnamon, thyme, taramira, oregano and rosemary at 1 µL/mL and 5 µL/mL for each E.O.As a matter of fact, their effects on the OTA production and the growth of A. carbonarius S402 cultures were evaluated, after four days at 28 °C on a Synthetic Grape Medium (SGM). Results showed that A. carbonarius growth was reduced up to 100%, when cultured with the E.Os of cinnamon, taramira, and oregano at both concentrations and the thyme at 5 µL/mL. As for the other six E.Os, their effect on A. carbonarius growth was insignificant, but highly important on the OTA production. Interestingly, the fennel E.O at 5 µL/mL reduced the OTA production up to 88.9% compared to the control, with only 13.8% of fungal growth reduction. We further investigated the effect of these E.Os on the expression levels of the genes responsible for the OTA biosynthesis (acOTApks and acOTAnrps along with the acpks gene) as well as the two regulatory genes laeA and vea, using the quantitative Reverse Transcription-Polymerase Chain Reaction (qRT-PCR) method. The results revealed that these six E.Os reduced the expression of the five studied genes, where the ackps was downregulated by 99.2% (the highest downregulation in this study) with 5 µL/mL of fennel E.O.As for the acOTApks, acOTAnrps, veA and laeA, their reduction levels ranged between 10% and 96% depending on the nature of the E.O and its concentration in the medium.


Removal of fluoride from fertilizer industry effluent using carbon nanotubes stabilized in chitosan sponge.
Adsorption of fluoride from fertilizer industry effluent using carbon nanotubes stabilized in chitosan sponge as adsorbent was evaluated. The effluent was produced in the washing of acid gases during the reaction in fertilizer production and all assays were performed using this hazardous material. Adsorbent characterization and ions interactions were elucidated from differential scanning calorimetry, thermal gravimetric analyses, X-ray diffraction, scanning electron microscopy dispersive energy X-ray spectroscopy, atomic force microscopy and X-ray photoelectron spectroscopy. The effluent presented pH 3 and its value not changed in the adsorption assays, maintaining the conditions of the process. The kinetics assays of fluoride from industry effluent were performed in different stirring rates from 100 to 300 rpm. It was observed that adsorption was initially fast reaching the equilibrium at 300 rpm in 20 min. The adsorption capacity was around 975.4 mg g-1, showing the potential of the hybrid material to remove fluoride from a real matrix. The high adsorption capacity was attributed to the chitosan functional groups and the high interaction area promoted by sponge form and the carbon nanotube. Reuse and regeneration of the CNT-CS were investigated and 5 cycles were obtained. The adsorption capacity kept similar values in all cycles.


NFATc3 is required for chronic hypoxia-induced pulmonary hypertension in adult and neonatal mice.
Pulmonary hypertension occurs with prolonged exposure to chronic hypoxia in both adults and neonates. The Ca(2+)-dependent transcription factor, nuclear factor of activated T cells isoform c3 (NFATc3), has been implicated in chronic hypoxia-induced pulmonary arterial remodeling in adult mice. Therefore, we hypothesized that NFATc3 is required for chronic hypoxia-induced pulmonary hypertension in adult and neonatal mice. The aim of this study was to determine whether 1) NFATc3 mediates chronic hypoxia-induced increases in right ventricular systolic pressure in adult mice; 2) NFATc3 is activated in neonatal mice exposed to chronic hypoxia; and 3) NFATc3 is involved in chronic hypoxia-induced right ventricular hypertrophy and pulmonary vascular remodeling in neonatal mice. Adult mice were exposed to hypobaric hypoxia for 2, 7, and 21 days. Neonatal mouse pups were exposed for 7 days to hypobaric chronic hypoxia within 2 days after delivery. Hypoxia-induced increases in right ventricular systolic pressure were absent in NFATc3 knockout adult mice. In neonatal mice, chronic hypoxia caused NFAT activation in whole lung and nuclear accumulation of NFATc3 in both pulmonary vascular smooth muscle and endothelial cells. In addition, heterozygous NFATc3 neonates showed less right ventricular hypertrophy and pulmonary artery wall thickness in response to chronic hypoxia than did wild-type neonates. Our results suggest that NFATc3 mediates pulmonary hypertension and vascular remodeling in both adult and neonatal mice.


Adjuvant therapy of breast cancer.
In the past few years the treatment of early stage breast cancer has gone through several important changes. Both chemotherapy and hormonal therapy have been shown by large, randomized trials to offer a survival advantage. The most commonly used chemotherapeutic agents used in the US are doxorubicin and cyclophosphamide (AC). However, 3 studies have suggested that there may be an advantage in the use of taxanes in the adjuvant treatment of breast cancer. Furthermore the use of dose dense chemotherapy, incorporating AC and paclitaxel, has shown very promising results. It is well established that tamoxifen (T), a selective estrogen receptor modulator (SERM), improves overall survival (OS) in women with hormone receptor (HR) positive breast cancer. However, the results from large multicenter, randomized trials, suggest the potential superiority of aromatase inhibitors (AIs), compared to T or an advantage of sequencing T followed by an AI. The role ovarian suppression is still being investigated in patients who have received prior chemotherapy. Newer agents, such as the monoclonal antibody against the her2/neu receptor, trastuzumab, are now being studied as adjuvant therapy in early stage breast cancer. In the next few years, with the completion of several large randomized trials, we will be able to answer several questions, including the optimal way of incorporating AIs into the adjuvant therapy, the long-term sequella of using trastuzumab in the adjuvant treatment of breast cancer and the role of ovarian suppression combined with an AI in premenopausal women with breast cancer.


Origin and emergence of the sweet dessert watermelon, Citrullus lanatus.
Watermelons, Citrullus species (Cucurbitaceae), are native to Africa and have been cultivated since ancient times. The fruit flesh of wild watermelons is watery, but typically hard-textured, pale-coloured and bland or bitter. The familiar sweet dessert watermelons, C. lanatus, featuring non-bitter, tender, well-coloured flesh, have a narrow genetic base, suggesting that they originated from a series of selection events in a single ancestral population. The objective of the present investigation was to determine where dessert watermelons originated and the time frame during which sweet dessert watermelons emerged. Archaeological remains of watermelons, mostly seeds, that date from 5000 years ago have been found in northeastern Africa. An image of a large, striped, oblong fruit on a tray has been found in an Egyptian tomb that dates to at least 4000 years ago. The Greek word pepon, Latin pepo and Hebrew avattiah of the first centuries CE were used for the same large, thick-rinded, wet fruit which, evidently, was the watermelon. Hebrew literature from the end of the second century CE and Latin literature from the beginning of the sixth century CE present watermelons together with three sweet fruits: figs, table grapes and pomegranates. Wild and primitive watermelons have been observed repeatedly in Sudan and neighbouring countries of northeastern Africa. The diverse evidence, combined, indicates that northeastern Africa is the centre of origin of the dessert watermelon, that watermelons were domesticated for water and food there over 4000 years ago, and that sweet dessert watermelons emerged in Mediterranean lands by approximately 2000 years ago. Next-generation ancient-DNA sequencing and state-of-the-art genomic analysis offer opportunities to rigorously assess the relationships among ancient and living wild and primitive watermelons from northeastern Africa, modern sweet dessert watermelons and other Citrullus taxa.


Protective effect of peroxisome proliferator-activated receptor-gamma agonists on activated renal proximal tubular epithelial cells in IgA nephropathy.
We have previously demonstrated a glomerulo-tubular 'crosstalk' operating in the pathogenesis of tubulointerstitial injury in IgA nephropathy (IgAN). The present study aims to explore any possible beneficial effect of a peroxisome proliferator-activated receptor-gamma (PPAR-gamma) agonist in alleviating the tubulointerstitial inflammation in IgAN. Human proximal tubular epithelial cells (PTEC) were pre-treated with increasing concentration of a PPAR-gamma agonist rosiglitazone or troglitazone (0-5 microM) followed by further incubation with the conditioned medium (IgA-HMC) collected from human mesangial cells (HMC) incubated with polymeric IgA isolated from IgAN patients. Gene expression of interleukin-6 (IL-6) and angiotensin II type 1 receptor (ATR1) was detected by reverse transcription-polymerase chain reaction (RT-PCR); protein expression of IL-6 and ATR1 was determined by ELISA and western blot, respectively. The mitogen-activated protein kinase extracellular signal-related kinase 1/2 (ERK1/2) activation was examined by western blot. An IgA-HMC conditioned medium prepared from IgAN patients increased gene expression and protein synthesis of IL-6 and ATR1 in PTEC when compared with a conditioned medium prepared from healthy controls. The upregulated gene expression and protein synthesis of IL-6 and ATR1 in PTEC induced by the IgA-HMC conditioned medium were readily attenuated following pre-treatment with a PPAR-gamma agonist, thiazolidinedione (TZD). The ATR1-downregulating effect exerted by the PPAR-gamma agonist occurred through the inhibition of ERK1/2 activation. The PPAR-gamma antagonist, GW9662, significantly attenuated the inhibitory action of rosiglitazone on the increased synthesis of IL-6 and ATR1 protein. Our current findings suggest that the PPAR-gamma agonist attenuates excessive inflammatory response in activated PTEC in IgAN through suppressing ATR1 expression. This ATR1-downregulating effect is likely through the inhibition of ERK1/2 activation and is found to be PPAR-gamma dependent. TZDs may possibly be new therapeutic additives to established treatment regime for renin-angiotensin system (RAS) blockade in IgAN.


Dietary protein intake and coronary heart disease in a large community based cohort: results from the Atherosclerosis Risk in Communities (ARIC) study [corrected].
Prospective data examining the relationship between dietary protein intake and incident coronary heart disease (CHD) are inconclusive. Most evidence is derived from homogenous populations such as health professionals. Large community-based analyses in more diverse samples are lacking. We studied the association of protein type and major dietary protein sources and risk for incident CHD in 12,066 middle-aged adults (aged 45-64 at baseline, 1987-1989) from four U.S. communities enrolled in the Atherosclerosis Risk in Communities (ARIC) Study who were free of diabetes mellitus and cardiovascular disease at baseline. Dietary protein intake was assessed at baseline and after 6 years of follow-up by food frequency questionnaire. Our primary outcome was adjudicated coronary heart disease events or deaths with following up through December 31, 2010. Cox proportional hazard models with multivariable adjustment were used for statistical analyses. During a median follow-up of 22 years, there were 1,147 CHD events. In multivariable analyses total, animal and vegetable protein were not associated with an increased risk for CHD before or after adjustment. In food group analyses of major dietary protein sources, protein intake from red and processed meat, dairy products, fish, nuts, eggs, and legumes were not significantly associated with CHD risk. The hazard ratios [with 95% confidence intervals] for risk of CHD across quintiles of protein from poultry were 1.00 [ref], 0.83 [0.70-0.99], 0.93 [0.75-1.15], 0.88 [0.73-1.06], 0.79 [0.64-0.98], P for trend = 0.16). Replacement analyses evaluating the association of substituting one source of dietary protein for another or of decreasing protein intake at the expense of carbohydrates or total fats did not show any statistically significant association with CHD risk. Based on a large community cohort we found no overall relationship between protein type and major dietary protein sources and risk for CHD.


Infertility: testing a helpseeking model.
This paper uses data from a study of 196 infertile women from the Midwestern US to examine a general theory of helpseeking behavior applied to infertility. All of these women report meeting the medical definition of infertility--12 months or more of regular intercourse without conception--at some point in their lives. Only 35 percent of this sample of infertile women identified themselves as having had fertility problems and only 40 percent had sought medical treatment. Drawing on prior theories of helpseeking, we examine the effects of symptom salience, life course cues, attitudes, predisposing factors, and enabling conditions on helpseeking. We posit a model in which a cognitive dimension (perceived infertility) mediates between these predictors and medical helpseeking. Symptom salience (experienced infertility while actively trying to get pregnant), low parity, and poor subjective health are significantly related to perceived infertility, which is, in turn, significantly associated with helpseeking for infertility. Supporting the conclusion that the cognitive dimension of identifying oneself as infertile is critical to helpseeking, the relationship of symptom salience to helpseeking is partially mediated by perceived problems. Internal health locus of control is associated with lower odds of helpseeking but not to perceived infertility.


Modeling of the generic spatial heterodyne spectrometer and comparison with conventional spectrometer.
We describe the modeling of the generic spatial heterodyne spectrometer. This instrument resembles a somewhat modified Michelson interferometer, in which the power spectrum of the input source is determined by performing a one-dimensional Fourier transform on the output intensity profile. Code has been developed to analyze the performance of this type of spectrometer by determining the dependence of both spectral resolution and throughput on parameters such as aperture and field of view. An example of a heterodyne spectrometer is developed to illustrate the techniques employed in the modeling and a comparison undertaken between its performance and that of a conventional spectrometer. Unlike the traditional Fourier transform infrared system, the heterodyne spectrometer has the very desirable feature of having no moving components.


Structure-based screening and molecular dynamics simulations offer novel natural compounds as potential inhibitors of Mycobacterium tuberculosis isocitrate lyase.
Mycobacterium tuberculosis is the etiological agent of tuberculosis in humans and is responsible for more than two million deaths annually. M. tuberculosis isocitrate lyase (MtbICL) catalyzes the first step in the glyoxylate cycle, plays a pivotal role in the persistence of M. tuberculosis, which acts as a potential target for an anti-tubercular drug. To identify the potential anti-tuberculosis compound, we conducted a structure-based virtual screening of natural compounds from the ZINC database (n = 1,67,748) against the MtbICL structure. The ligands were docked against MtbICL in three sequential docking modes that resulted in 340 ligands having better docking score. These compounds were evaluated for Lipinski and ADMET prediction, and 27 compounds were found to fit well with re-docking studies. After refinement by molecular docking and drug-likeness analyses, three potential inhibitors (ZINC1306071, ZINC2111081, and ZINC2134917) were identified. These three ligands and the reference compounds were further subjected to molecular dynamics simulation and binding energy analyses to compare the dynamic structure of protein after ligand binding and the stability of the MtbICL and bound complexes. The binding free energy analyses were calculated to validate and capture the intermolecular interactions. The results suggested that the three compounds had a negative binding energy with -96.462, -143.549, and -122.526 kJ mol-1 for compounds with IDs ZINC1306071, ZINC2111081, and ZINC2134917, respectively. These lead compounds displayed substantial pharmacological and structural properties to be drug candidates. We concluded that ZINC2111081 has a great potential to inhibit MtbICL and would add to the drug discovery process against tuberculosis.


Studying the drift of in line pH measurements in cell culture.
The culture of Chinese hamster ovary (CHO) cells to produce monoclonal antibodies (MAb) requires accurate measurement and control of pH. Unwanted pH drifts in cell culture can adversely affect process performance, product quality, and product yield. To measure and control pH throughout the length of a culture, most cell culture processes use traditional glass pH probes. Several variables can affect the design and performance of glass pH electrodes and lead to drift in the measurement. Understanding these variables and their effects on pH performance can lead to design improvements and potentially reduce the drift. In this study, a set of Rosemount Analytical glass pH probes was investigated in cell culture operations. Electrochemical properties of the probes were monitored throughout the experiments. Experimental results show that the glass membrane potential experiences the biggest change during cell culture operations. Changes in the reference electrode potential are small compared with the changes in glass membrane potential. The glass membranes are affected by the steam sterilization process and this is the main cause for drift in the probe sensing signal during cell culture operations. Steam sterilization can cause the potential of glass membranes to change by up to 15 mV (∼ 0.25 pH units). This change in membrane potential can be observed as an undesirable pH drift in bioreactors.


Anemia, hematinic deficiencies, hyperhomocysteinemia, and gastric parietal cell antibody positivity in atrophic glossitis patients with iron deficiency.
Our previous study found that 180 of 1064 atrophic glossitis (AG) patients have iron deficiency. This study assessed whether all AG patients with iron deficiency (so-called ID/AG patients) had iron deficiency anemia (IDA) and evaluated whether the ID/AG patients had significantly higher frequencies of anemia, hematinic deficiencies, hyperhomocysteinemia, and serum gastric parietal cell antibody (GPCA) positivity than healthy control subjects. The blood hemoglobin (Hb) and serum iron, vitamin B12, folic acid, homocysteine, and GPCA levels in 180 ID/AG patients and 532 healthy control subjects were measured and compared. We found that 180 ID/AG patients had significantly lower mean corpuscular volume (MCV) and lower mean blood Hb and serum iron levels as well as significantly higher mean serum homocysteine level than healthy control subjects (all P-values < 0.001). Moreover, 180 ID/AG patients had significantly higher frequencies of blood Hb (46.1%), serum iron (100.0%), vitamin B12 (8.3%), and folic acid (4.4%) deficiencies, hyperhomocysteinemia (16.1%), and serum GPCA positivity (31.1%) than 532 healthy control subjects (all P-values < 0.001). In addition, of 83 anemic ID/AG patients, 9 (10.8%) had pernicious anemia, 40 (48.2%) had normocytic anemia, 30 (36.2%) had IDA, and 4 (4.8%) had thalassemia trait-induced anemia. We conclude that ID/AG patients had significantly higher frequencies of blood Hb, serum iron, vitamin B12, and folic acid deficiencies, hyperhomocysteinemia, and serum GPCA positivity than 532 healthy control subjects. Normocytic anemia is the most common type of anemia in ID/AG patients, followed by IDA, pernicious anemia, and thalassemia trait-induced anemia.


Experience of a single center with congenital hepatic fibrosis: a review of the literature.
Congenital hepatic fibrosis (CHF) is an autosomal recessive inherited malformation defined pathologically by a variable degree of periportal fibrosis and irregularly shaped proliferating bile ducts. It is one of the fibropolycystic diseases, which also include Caroli disease, autosomal dominant polycystic kidney disease, and autosomal recessive polycystic kidney disease. Clinically it is characterized by hepatic fibrosis, portal hypertension, and renal cystic disease. CHF is known to occur in association with a range of both inherited and non-inherited disorders, with multiorgan involvement, as a result of ductal plate malformation. Because of the similarities in the clinical picture, it is necessary to differentiate CHF from idiopathic portal hypertension and early liver cirrhosis, for which a liver biopsy is essential. Radiological tests are important for recognizing involvement of other organ systems. With regards to our experience at Hacettepe University, a total of 26 patients have been diagnosed and followed-up between 1974 and 2009 with a diagnosis of CHF. Presentation with Caroli syndrome was the most common diagnosis, with all such patients presenting with symptoms of recurrent cholangitis and symptoms related to portal hypertension. Although portal fibrosis is known to contribute to the ensuing portal hypertension, it is our belief that portal vein cavernous transformation also plays an important role in its pathogenesis. In all patients with CHF portal vein morphology should be evaluated by all means since portal vein involvement results in more severe and complicated portal hypertension. Other associations include the Joubert and Bardet-Biedl syndromes.


Tbx1 regulates proliferation and differentiation of multipotent heart progenitors.
TBX1 encodes a T-box transcription factor implicated in DiGeorge syndrome, which affects the development of many organs, including the heart. Loss of Tbx1 results into hypoplasia of heart regions derived from the second heart field, a population of cardiac progenitors cells (CPCs). Thus, we hypothesized that Tbx1 is an important player in the biology of CPCs. We asked whether Tbx1 is expressed in multipotent CPCs and, if so, what role it may play in them. We used clonal analysis of Tbx1-expressing cells and loss and gain of function models, in vivo and in vitro, to define the role of Tbx1 in CPCs. We found that Tbx1 is expressed in multipotent heart progenitors that, in clonal assays, can give rise to 3 heart lineages expressing endothelial, smooth muscle and cardiomyocyte markers. In multipotent cells, Tbx1 stimulates proliferation, explaining why Tbx1(-/-) embryos have reduced proliferation in the second heart field. In this population, Tbx1 is expressed while cells are undifferentiated and it disappears with the onset of muscle markers. Loss of Tbx1 results in premature differentiation, whereas gain results in reduced differentiation in vivo. We found that Tbx1 binds serum response factor, a master regulator of muscle differentiation, and negatively regulates its level. The Tbx1 protein marks CPCs, supports their proliferation, and inhibits their differentiation. We propose that Tbx1 is a key regulator of CPC homeostasis as it modulates positively their proliferation and negatively their differentiation.


How to evade a coevolving brood parasite: egg discrimination versus egg variability as host defences.
Arms races between avian brood parasites and their hosts often result in parasitic mimicry of host eggs, to evade rejection. Once egg mimicry has evolved, host defences could escalate in two ways: (i) hosts could improve their level of egg discrimination; and (ii) negative frequency-dependent selection could generate increased variation in egg appearance (polymorphism) among individuals. Proficiency in one defence might reduce selection on the other, while a combination of the two should enable successful rejection of parasitic eggs. We compared three highly variable host species of the Afrotropical cuckoo finch Anomalospiza imberbis, using egg rejection experiments and modelling of avian colour and pattern vision. We show that each differed in their level of polymorphism, in the visual cues they used to reject foreign eggs, and in their degree of discrimination. The most polymorphic host had the crudest discrimination, whereas the least polymorphic was most discriminating. The third species, not currently parasitized, was intermediate for both defences. A model simulating parasitic laying and host rejection behaviour based on the field experiments showed that the two host strategies result in approximately the same fitness advantage to hosts. Thus, neither strategy is superior, but rather they reflect alternative potential evolutionary trajectories.


Unexpected complication of oesophagoscopy: iatrogenic aortic injury in a child.
Oesophagoscopy is usually a safe procedure to localise and remove ingested foreign bodies, however, unexpected complications may develop during this procedure. In this case report we discuss iatrogenic aortic injury, which developed during oesophagoscopy, and its immediate treatment. A six-year-old male patient was admitted to hospital with symptoms of having ingested a foreign body. Oesophagoscopy was carried out and the foreign body was visualised at the second constriction of the oesophagus. During this procedure, profuse bleeding occurred. Subsequently, a balloon dilator was placed to control bleeding in the oesophagus. Thoracic contrast tomography revealed thoracic aortic injury. Open surgical aortic repair was immediately carried out on the patient and the oesophageal hole was primarily repaired. The patient was discharged on postoperative day 15 with a total cure. Although oesophagoscopy is a safe, easily applied method, it should be kept in mind that fatal complications may occur during the procedure. This procedure should be done in high-level medical centres, which have extra facilities for managing complications.


Human immunodeficiency virus type 1 neutralization is determined by epitope exposure on the gp120 oligomer.
The major target of the neutralizing antibody response to infection by the human immunodeficiency virus type 1 (HIV-1) is the outer envelope glycoprotein, gp120. The spectrum of HIV-1 neutralization specificity is currently represented by monoclonal antibodies (mAbs) that can be divided broadly into five groups. We have studied the binding of these mAbs to functional oligomeric and soluble monomeric gp120 derived from the molecular clone of a cell line-adapted isolate of HIV-1, and compared these binding properties with virus neutralization. Binding of all mAbs except those reactive with the V3 loop was much weaker to oligomeric than to monomeric gp120. This reduction in binding to oligomeric gp120 was determined mostly by a slower relative rate of association, although the dissociation rate also had some influence on relative variation in mAb affinity. Virus neutralization correlated broadly with mAb binding to the oligomeric rather than to the monomeric form of gp120, and neutralization potency was related to the estimated association rate. Thus, with the exception of the hypervariable V3 loop, regions of HIV-1 gp120 with the potential to induce a neutralization response are likely to be poorly presented for antibody recognition on the surface of cell line-adapted virions.


Mortality associated with tiotropium mist inhaler in patients with chronic obstructive pulmonary disease: systematic review and meta-analysis of randomised controlled trials.
To systematically review the risk of mortality associated with long term use of tiotropium delivered using a mist inhaler for symptomatic improvement in chronic obstructive pulmonary disease. Medline, Embase, the pharmaceutical company clinical trials register, the US Food and Drug Administration website, and ClinicalTrials.gov for randomised controlled trials from inception to July 2010. Trials were selected for inclusion if they were parallel group randomised controlled trials of tiotropium solution using a mist inhaler (Respimat Soft Mist Inhaler, Boehringer Ingelheim) versus placebo for chronic obstructive pulmonary disease; the treatment duration was more than 30 days, and they reported data on mortality. Relative risks of all cause mortality were estimated using a fixed effect meta-analysis, and heterogeneity was assessed with the I(2) statistic. Five randomised controlled trials were eligible for inclusion. Tiotropium mist inhaler was associated with a significantly increased risk of mortality (90/3686 v 47/2836; relative risk 1.52, 95% confidence interval, 1.06 to 2.16; P = 0.02; I(2) = 0%). Both 10 µg (2.15, 1.03 to 4.51; P = 0.04; I(2) = 9%) and 5 µg (1.46, 1.01 to 2.10; P = 0.04; I(2) = 0%) doses of tiotropium mist inhaler were associated with an increased risk of mortality. The overall estimates were not substantially changed by sensitivity analysis of the fixed effect analysis of the five trials combined using the random effects model (1.45, 1.02 to 2.07; P = 0.04), limiting the analysis to three trials of one year's duration each (1.50, 1.05 to 2.15), or the inclusion of additional data on tiotropium mist inhaler from another investigational drug programme (1.42, 1.01 to 2.00). The number needed to treat for a year with the 5 µg dose to see one additional death was estimated to be 124 (95% confidence interval 52 to 5682) based on the average control event rate from the long term trials. This meta-analysis explains safety concerns by regulatory agencies and indicates a 52% increased risk of mortality associated with tiotropium mist inhaler in patients with chronic obstructive pulmonary disease.


The impact of previous ureteroscopic tumor ablation on oncologic outcomes after radical nephrouretectomy for upper urinary tract urothelial carcinoma.
Abstract We investigated whether a history of endoscopic tumor ablation impacts oncologic outcomes after radical nephroureterectomy (RNU) for upper urinary tract urothelial carcinoma (UTUC). Using a multi-institutional database that contained patients who were treated with RNU, oncologic outcomes were assessed according to history of ureteroscopic tumor ablation. Disease-free survival (DFS) and cancer-specific survival (CSS) were estimated using the Kaplan-Meier survival analysis. Multivariate Cox regression analyses were performed to determine independent predictors of disease recurrence and cancer-specific mortality after RNU. The study included 1268 patients, 853 men and 415 women, with a mean age of 67.5 years (range 32-94 y) and 52.8 months median follow-up after RNU. A total of 175 (13%) patients underwent RNU after endoscopic tumor ablation and 1093 (87%) patients underwent RNU without a history of endoscopic ablation. The 5-year DFS and CSS rates were 72% and 77% in those with a history of tumor ablation vs 69% and 73% in those without a history of ablation (P = 0.171 and P = 0.365, respectively). In multivariate Cox regression analysis, history of ablation therapy was not associated with disease recurrence or cancer-specific mortality (hazard ratio [HR]: 0.79, P = 0.185 and HR: 0.7, P = 0.078, respectively). Our collaborative international efforts suggest that in selected patients, endoscopic tumor ablation does not adversely affect the recurrence and survival after subsequent RNU for UTUC. Our data support the continued role of ureteroscopic ablation of UTUC in appropriately selected patients.


A glycyrrhizin-containing preparation reduces hepatic steatosis induced by hepatitis C virus protein and iron in mice.
A European randomized trial showed biochemical effects of 6-month treatment with Stronger Neo-Minophagen C (SNMC), a glycyrrhizin-containing preparation, in patients with chronic hepatitis C, but its underlying mechanisms remain elusive. We reported previously that SNMC exhibits an anti-oxidative effect in hepatitis C virus (HCV) transgenic mice that develop marked hepatic steatosis with mitochondrial injury under iron overloading. Hepatic steatosis and iron overload are oxidative stress-associated pathophysiological features in chronic hepatitis C. The aim of this study was to investigate whether long-term treatment with SNMC could prevent the development of hepatic steatosis in iron-overloaded HCV transgenic mice. C57BL/6 transgenic mice expressing the HCV polyprotein were fed an excess iron diet concomitantly with intraperitoneal injection of saline, SNMC, or seven-fold-concentrated SNMC thrice weekly for 6 months. Stronger Neo-Minophagen C inhibited the development of hepatic steatosis in a dose-dependent manner without affecting hepatic iron content, attenuated ultrastructural alterations of mitochondria of the liver, activated mitochondrial β-oxidation with increased expression of carnitine palmitoyl transferase I and decreased the production of reactive oxygen species in the liver in iron-overloaded transgenic mice. However, SNMC hardly affected the unfolded protein response, which post-transcriptionally activates sterol regulatory element-binding protein 1, a transcription factor involved in lipid synthesis, even though we reported previously the activation of the unfolded protein response in the same iron-overloaded transgenic mice. These results suggest that SNMC prevents hepatic steatosis possibly by protecting mitochondria against oxidative stress induced by HCV proteins and iron overload.


Health care and social service professionals' perceptions of a home-visit program for young, first-time mothers.
Little is known about health care and social service professionals' perspective on the acceptability of long-term home-visit programs serving low-income, first-time mothers. This study describes the experiences and perspectives of these community care providers involved with program referrals or service delivery to mothers who participated in the Nurse-Family Partnership (NFP), a targeted nurse home-visit program. The study included two phases. Phase I was a secondary qualitative data analysis used to analyze a purposeful sample of 24 individual interviews of community care providers. This was part of a larger case study examining adaptations required to increase acceptability of the NFP in Hamilton, Ontario, Canada. In Phase II (n = 4), themes identified from Phase I were further explored through individual, semi-structured interviews with community health care and social service providers, giving qualitative description. Overall, the NFP was viewed as addressing an important service gap for first-time mothers. Providers suggested that frequent communication between the NFP and community agencies serving these mothers could help improve the referral process, avoid service duplication, and streamline the flow of service access. The findings can help determine key components required to enhance the success of integrating a home-visit program into an existing network of community services. The function of home-visit programs should not be viewed in isolation. Rather, their potential can be maximized when they collaborate and share information with other agencies to provide better services for first-time mothers.


Relationship between clonogenic radiosensitivity, radiation-induced apoptosis and DNA damage/repair in human colon cancer cells.
The intrinsic radiation sensitivity of normal and tumour tissue is a major determinant of the outcome of radiotherapy. There is currently no established test that can be used routinely to measure the radiosensitivity of the cells in an individual patient's cancer in a manner that can inform treatment planning. The purpose of this study was to evaluate, in four human colorectal adenocarcinoma cell lines, two possible end points as surrogate markers of radiation response--apoptosis and induction of DNA single-strand breaks--and to compare the results with those of a conventional clonogenic assay. Cell lines (SW707 SW480, SW48 and HT29) known to differ in radiosensitivity were exposed to single doses of X-rays ranging from 0.5 to 5 Gy and cell survival was measured using the clonogenic assay. Apoptosis was determined on the basis of morphology under fluorescent microscopy and DNA damage/repair was measured, as tail moment, using an adaptation of the alkaline comet assay. The relationship between surviving fraction at 2 Gy (SF2) and the percentage of apoptotic cells 24 h after the same dose was complex, but apoptosis accurately predicted the order of radiosensitivities as measured by SF2. Initial damage measured after 2 Gy using the alkaline comet assay gave a close correlation with SF2 (r2=0.95), whereas there was no correlation between initial DNA damage repair rate and SF2.


Patients with tuberculosis in Bolivia: why do they die?
The objective of this research was to analyze why patients with tuberculosis (TB) die and to evaluate whether there are factors contributing to their fatal outcome that could be corrected. A cross-sectional observational study was conducted of the patients with active TB or its sequelae admitted to the TB ward of the main public hospital in the city of Santa Cruz, Bolivia, over a 29-month period, from October 1993 through February 1996. The available records of the patients who died during hospitalization were reviewed. Out of 597 patients, 94 of them (15.7%) died. We examined the records of 90 of these 94 patients. Their mean age was 35.1 years (standard deviation, 16.7 years), and 45 of the patients (50.0%) were male. On admission 42 of the 90 patients (46.7%) had never been treated for TB or had received anti-TB treatment for less than one month, 23 (25.6%) had returned after having abandoned their TB treatment, 8 (8.9%) had had an erroneous diagnosis, 6 (6.7%) had tuberculosis sequelae, 6 (6.7%) were undergoing tuberculosis treatment, and 5 (5.6%) were known to have multidrug-resistant TB. Of the 90 patients, 83 (92.2%) had pulmonary tuberculosis (median lobes affected, 4), 6 (6.7%) had pleural tuberculosis, and 12 (13.3%) had extrapulmonary tuberculosis (some patients had more than one form of TB). Patients died a median of 5.5 days after entering the TB ward. The causes of death were: hemoptysis, 6 patients (6.7%); other tuberculosis-related causes, 65 patients (72.2%); drug reactions, 6 patients (6.7%); nontuberculosis causes, 6 patients (6.7%); and undetermined causes, 7 patients (7.8%). Factors possibly contributing to death were late diagnosis (38.9%), errors in follow-up (14.4%), and errors in treatment (24.4%). In conclusion, most patients with active or inactive TB admitted to our ward died as a consequence of tuberculosis. There were several factors possibly contributing to their fatal outcome that could be corrected.


Polymeric structure of spruce lignin.
From the Flory-Stockmayer theory and molecular weights of successive fractions of lignin obtained by extraction of spruce wood with a mixture of water, dioxane, and hydrochloric acid and by sulfonation, the average length of the primary chains was estimated to be 18 phenylpropane units. From data on the acid-catalyzed cleavage of model compounds in various solvents the degrees of cross-linking in four extraction processes were calculated. The average degree of cross-linking of intact lignin was found to be 0.277; that is, 5 out of every 18 phenylpropane units bear cross-linking benzyl ether groups. Of the five, three are also etherified at their phenolic ends (B groups), and two are not (X groups).


EIF4G1 is neither a strong nor a common risk factor for Parkinson's disease: evidence from large European cohorts.
Missense mutations in the eukaryotic translation initiation factor 4-γ 1 (EIF4G1) gene have previously been implicated in familial Parkinson's disease (PD). A large PD family with autosomal-dominant segregation showed a heterozygous missense mutation and additional patients were found to have unique sequence variants that have not been observed in controls. Subsequent studies have reported contradictory findings. We assessed the relevance of EIF4G1 mutations in a European cohort of 2146 PD patients. Of these, 2051 sporadic PD patients were screened for the reported p.Ala502Val and p.Arg1205His mutations. In addition, the complete coding region of EIF4G1 was directly sequenced in 95 familial PD patients with autosomal-dominant inheritance. Moreover, we imputed the p.Arg1205His substitution and tested for association with PD in the Icelandic population (93 698 samples). We did not observe the presence of the p.Ala502Val substitution in our cohort; however, the p.Arg1205His mutation was identified in one sporadic PD patient. The same mutation was also found in 76 Icelandic subjects older than 65 years using haplotype imputing. Only five of these subjects reported PD symptoms (OR 1.3, p=0.50). Thus, if causal, the p.Arg1205His EIF4G1 mutation has a low penetrance or a late onset manifestation. A novel variant p.Arg566Cys found in a patient with familial PD did not cosegregate with PD in all three affected siblings. All further recently published EIF4G1 mutations found in our cohort are likely to be benign polymorphisms. This is the largest genetic study of EIF4G1 mutations in PD. Our data do not support the EIF4G1 gene as a high-risk PD locus, neither for the familial nor the sporadic condition. Furthermore, the p.Arg1205His mutation is not significantly associated with increased risk of PD in the Icelandic population. Therefore, caution should be exercised when interpreting EIF4G1 genotyping results in isolated patients and PD families. In summary, diagnostic testing of EIF4G1 should not be recommended in clinical settings.


Providers' Experiences with a Melanoma Web-Based Course: a Discussion on Barriers and Intentions.
Primary care visits provide an opportunity for skin examinations with the potential to reduce melanoma mortality. The INFORMED (INternet curriculum FOR Melanoma Early Detection) Group developed a Web-based curriculum to improve primary care providers' (PCPs') skin cancer detection skills. This study details feedback obtained from participant focus groups, including the feasibility of implementing in other PCP practices. Practicing PCPs at Henry Ford Health System and Kaiser Permanente Northern California completed the curriculum. Feedback sessions were conducted with standardized questions focusing on four domains: (1) overall impressions of the curriculum, (2) recommendations for improvement, (3) current skin examination practices, and (4) suggestions for increasing skin screening by PCPs. Discussions at each site were audio recorded, transcribed verbatim, and de-identified. Providers (N = 54) had a positive impression of the Web-based curriculum, with suggestions to provide offline teaching aids and request assistance. Despite having improved confidence in diagnosing malignant lesions, many providers felt a lack of confidence in performing the screening and time constraints affected their current practices, as did institutional constraints. Providers intended to increase discussion with patients about skin cancer. The accessibility, effectiveness, and popularity of the curriculum indicate potential for implementation in the primary care setting. Participating providers noted that institutional barriers remain which must be addressed for successful dissemination and implementation.


Defying bacteriophages: Contrasting altruistic with individual-based resistance mechanisms in Escherichia coli.
Adaptations by hosts in response to parasitism are generally believed to reduce the susceptibility of the adapted individual. However, recent work on Escherichia coli showed that bacteria can fight deadly phage attacks by committing altruistic suicide upon infection, in order to prevent parasite transmission to nearby relatives. Here, we compare the efficiency of suicidal host defense with individual-based resistance. We show that in unstructured environments suicidal host defense is futile since suicide cannot preferentially protect relatives, whereas individual-based resistance is highly efficient in defying phages. In contrast, we found that in structured environments suicidal host defense and individual-based resistance were both efficient in withstanding phages, with the latter type performing slightly better. We propose that the putative lower efficiency of suicidal host defense might be compensated by the fact that suicidal systems usually do not bear pleiotropic costs of resistance, as it is usually the case for individual-based resistance mechanisms.


Self-identification with another person's face: the time relevant role of multimodal brain areas in the enfacement illusion.
The illusory subjective experience of looking at one's own face while in fact looking at another person's face can surprisingly be induced by simple synchronized visuotactile stimulation of the two faces. A recent study (Apps MA, Tajadura-Jiménez A, Sereno M, Blanke O, Tsakiris M. Cereb Cortex. First published August 20, 2013; doi:10.1093/cercor/bht199) investigated for the first time the role of visual unimodal and temporoparietal multimodal brain areas in the enfacement illusion and suggested a model in which multisensory mechanisms are crucial to construct and update self-face representation.


Spectrally tailored narrowband pulses for femtosecond stimulated Raman spectroscopy in the range 330-750 nm.
Spectral compression of femtosecond pulses by second harmonic generation in the presence of substantial group velocity dispersion provides a convenient source of narrowband Raman pump pulses for femtosecond stimulated Raman spectroscopy (FSRS). We discuss here a simple and efficient modification that dramatically increases the versatility of the second harmonic spectral compression technique. Adding a spectral filter following second harmonic generation produces narrowband pulses with a superior temporal profile. This simple modification i) increases the Raman gain for a given pulse energy, ii) improves the spectral resolution, iii) suppresses coherent oscillations associated with slowly dephasing vibrations, and iv) extends the useful tunable range to at least 330-750 nm.


Putative functions of extracellular matrix glycoproteins in secondary palate morphogenesis.
Cleft palate is a common birth defect in humans. Elevation and fusion of paired palatal shelves are coordinated by growth and transcription factors, and mutations in these can cause malformations. Among the effector genes for growth factor signaling are extracellular matrix (ECM) glycoproteins. These provide substrates for cell adhesion (e.g., fibronectin, tenascins), but also regulate growth factor availability (e.g., fibrillins). Cleft palate in Bmp7 null mouse embryos is caused by a delay in palatal shelf elevation. In contrast, palatal shelves of Tgf-β3 knockout mice elevate normally, but a cleft develops due to their failure to fuse. However, nothing is known about a possible functional interaction between specific ECM proteins and Tgf-β/Bmp family members in palatogenesis. To start addressing this question, we studied the mRNA and protein distribution of relevant ECM components during secondary palate development, and compared it to growth factor expression in wildtypewild type and mutant mice. We found that fibrillin-2 (but not fibrillin-1) mRNA appeared in the mesenchyme of elevated palatal shelves adjacent to the midline epithelial cells, which were positive for Tgf-β3 mRNA. Moreover, midline epithelial cells started expressing fibronectin upon contact of the two palatal shelves. These findings support the hypothesis that fibrillin-2 and fibronectin are involved in regulating the activity of Tgf-β3 at the fusing midline. In addition, we observed that tenascin-W (but not tenascin-C) was misexpressed in palatal shelves of Bmp7-deficient mouse embryos. In contrast to tenascin-C, tenascin-W secretion was strongly induced by Bmp7 in embryonic cranial fibroblasts in vitro. These results are consistent with a putative function for tenascin-W as a target of Bmp7 signaling during palate elevation. Our results indicate that distinct ECM proteins are important for morphogenesis of the secondary palate, both as downstream effectors and as regulators of Tgf-β/Bmp activity.


Characterisation of a second protein encoded by the differentially regulated LmcDNA16 gene family of Leishmania major.
The LmcDNA16 gene family of Leishmania major contains five genes: three highly related sequences, genes A, B and C, and a tandem pair of unrelated sequences, genes D1 and D2. Previous studies have demonstrated that gene B codes for a novel, hydrophilic protein that is present on the surface of infective parasite stages at approximately 10(5) copies per call. This paper describes the identification and characterisation of a second protein encoded by this gene array: the 7.6 kDa A/C protein. This molecule shares considerable amino acid identity with the gene B protein (GBP) but lacks the characteristic proline rich amino acid repeat region. Like GBP, the A/C protein is expressed on the surface of infective metacyclic parasites, despite the lack of conventional signal and anchor sequences. It has previously been suggested that the GBP repetitive sequence plays a role in mediating protein attachment to the parasite surface. It now appears more likely that the conserved amino- and/or carboxyl-terminal domains of the A/C and B proteins are involved in this process.


Clinician percent syllables stuttered, clinician severity ratings and speaker severity ratings: are they interchangeable?
At present, percent syllables stuttered (%SS) is the gold standard outcome measure for behavioural stuttering treatment research. However, ordinal severity rating (SR) procedures have some inherent advantages over that method. To establish the relationship between Clinician %SS, Clinician SR and self-reported Speaker SR. To investigate whether Clinician SRs and Speaker SRs can be used interchangeably. Participants were three experienced speech-language pathologist (SLP) judges and 87 adults who stuttered. Adults who stuttered received a 10-min unscheduled telephone call at the conclusion of which they self-reported a SR using a nine-point scale. The SLPs measured the stuttering for these conversations with %SS and also with the SR scale. The mean scores for Clinician %SS and Clinician SR were compared with Speaker SR using appropriate indices of relative and absolute reliability. Relative reliability indices deal with the rank order of participants in a sample and whether they can be distinguished from each other. However, absolute reliability indices are related to the closeness of the measurement scores to each other and to a hypothetical true score. Strong correlations were found between Clinician %SS and Clinician SR, and also between Clinician %SS and Speaker SR, although with higher values in the former case. Additionally, very high correlations showed acceptable relative reliability between Clinician SR and Speaker SR. However, absolute reliability in terms of standard error of measurement and limits of agreement was poor for Clinician SR and Speaker SR. The results suggest that Clinician SR and Speaker SR cannot be used interchangeably to measure temporal stuttering severity changes for an individual client. However, researchers might use these two measures interchangeably in research contexts, such as clinical trials, where changes of the entire group are of interest to determine and compare treatment effect size across trials.


Cardiac Events Within the 30-Day Postoperative Period Is Associated With Increased 1-Year Mortality Among Deceased-Donor Liver Transplant Recipients.
Each year in the United States, approximately 40000 patients with a liver disorder will progress to end-stage liver disease and about 30000 of those patients will subsequently die from this condition. Liver transplant remains the definitive treatment option for end-stage liver disease, and understanding the causes of posttransplant mortality is an ongoing area of investigation. In this retrospective cohort study, patients who underwent orthotopic liver transplant between January 2012 and January 2015 at the Johns Hopkins Hospital Liver Transplant Program were reviewed by a single reviewer for cardiac events in the 30 days after transplant or during the index admission. Of the 145 patients included, 30 (20.6%) were identified as having experienced a cardiac event during the defined postoperative period. Overall 1-year mortality for the cohort of 145 patients was 11.7%; however, 1-year mortality in those who had a cardiac event was 36.7% compared with 5.2% in the noncardiac event group (odds ratio = 18.17; P < .001). Although there was a statistically significant difference in age between the groups (58.6 vs 52.3 years old), once accounted for in multivariate analysis, a posttransplant cardiac event was still a statistically significant variable in 1-year mortality (odds ratio = 89.16; 95% confidence interval, 2.71-2933.95; P = .012). Similarly, hepatocellular carcinoma, sex, age, and presence of diabetes had little effect on 1-year mortality when we compared those patients who experienced a cardiac event in the first 30 days versus those who did not (odds ratio = 100.82; 95% confidence interval, 2.15-4726.12; P = .019). Recipients who experience cardiac events within 30 days after transplant have increased 1-year posttransplant mortality. This highlights the importance of cardiac risk stratification before transplant.


The current perception threshold test differentiates categories of mechanical neck disorder.
Cross-sectional discriminative analysis. To determine whether current perception threshold (CPT) can differentiate between categories of patients with mechanical neck disorders (MNDs). Neck pain is the third most common musculoskeletal disorder and affects a third of all adults each year. It can present as neck pain without musculoskeletal signs, neck pain with musculoskeletal signs but no neurological signs, or neck pain with neurological signs. CPT testing can assess altered sensory perception that may reflect neurological changes. Patients with MNDs (n = 106) were classified into 3 groups, based on a standardized musculoskeletal examination process performed by an experienced physiotherapist who was blinded to CPT scores. The 3 groups were defined as neck pain without musculoskeletal signs (MND I) (n = 60), neck pain with musculoskeletal signs (MND II) (n = 29), and neck pain with neurological signs (MND III) (n = 17). A rapid protocol of CPT testing was performed at 3 frequencies (5, 250, and 2000 Hz), using 3 dermatomal locations on the hand. A 1-way analysis of variance with post hoc comparison and effect sizes was calculated to compare the mean CPT scores between the groups. A binary logistic-regression model was used to predict probability of higher CPT in MND III and to create a receiver-operating-characteristic curve. Mean CPT differed significantly across the 3 MND groups (MND I, 9.7; MND II, 10.6; and MND III, 11.8; P<.001; η(2) = 0.6). Post hoc comparisons indicated differences between MND I and MND II (P = .05) and between MND II and MND III (P = .01) that had large effect sizes (MND I versus II, d = 1 and MND II versus III, d = 2.2). CPT testing was able to distinguish between MND II and III when a threshold value of greater than 11 was used to indicate MND III. The predicted probability of abnormal CPT in MND III had an estimated 73% sensitivity and 81% specificity; the odds ratio was 11.5 (P = .001) for the differentiation capacity of CPT between MND II and III, with a cutoff of 11. The area under the receiver-operating-characteristic curve was 0.84 (95% confidence interval: 0.72, 0.96; P<.001). CPT testing has moderate discriminatory accuracy, specificity, and sensitivity for classification of MND categories into neck pain with or without neurological signs. J Orthop Sports Phys Ther 2014;44(7):532-540. Epub 10 May 2014. doi:10.2519/jospt.2014.4691.


Network Meta-Analysis of Various Nonpharmacological Interventions on Pain Relief in Older Adults With Osteoarthritis.
To compare the effectiveness of different nonpharmacological interventions on pain relief in older adults with osteoarthritis, literature databases, bibliographies, and other relevant sources were searched. No language limitations were applied. Thirty-two trials published from 1997 to 2017 were included in the systematic review and network meta-analyses. We included only randomized controlled trials and studies that evaluated the effects of nonpharmacological interventions on alleviating pain in elderly adults (age ≥60 yrs or mean age > 65 yrs) who experience osteoarthritis, irrespective of sex. In the network meta-analysis, resistance training was ranked as the most effective among all nonpharmacological interventions (surface under the cumulative ranking = 82.9%, standardized mean difference = 1.96, confidence interval = -1.39 to 5.31). In subgroup analyses, resistance training still ranked the most effective pain reduction intervention, followed by strengthening exercise and yoga. Among female subjects with intervention adherence rate more than 90%, the most effective intervention was yoga. Strengthening exercise was superior to all other forms of interventions when comparing long-term effect of selected interventions. Among older adults with osteoarthritis, resistance training can be considered a treatment option for pain relief. Yoga is an effective intervention strategy for female elderly, and strengthening exercise has a better long-term beneficial effect.


Induction of antiphosphorylcholine antibody formation by anti-idiotypic antibodies.
Anti-idiotypic antibodies have been used to mimic antigen in the mouse antiphosphorylcholine response in order to investigate the induction of precursors of antibody-forming cells. We have shown that interaction of anti-idiotype antibody with receptor antibody molecules induces the formation of antibodies that are specific for phosphorylcholine and carry the idiotypic determinants. This induction is dependent on the recognition of carrier determinants on the anti-idiotype antibody by helper T cells. We conclude that receptor antibody molecules on the surface of the precursors of antibody-forming cells deliver the antigenic signal for the induction of these cells.


HIV-associated nephropathy: experimental models.
Since 1984 reports of renal involvement in AIDS patients have been presented in the literature. Different forms of renal disease were noted in the AIDS population including those related to systemic and local renal infections, tubulointerstitial disease, renal involvement by neoplasm and glomerular disease including collapsing glomerulopathy (CG). HIV-associated nephropathy (HIVAN) has been demonstrated to be more severe in the black population. HIVAN is the most common cause of renal failure in HIV-1-seropositive patients. The term HIVAN is reserved for the typical histopathological form of focal and segmental glomerulosclerosis (FSGS) characterized by the findings of coexistent glomerular and severe tubulointerstitial disease. In both humans and the murine model, glomerular lesions include FSGS, glomerular collapse and podocyte hyperplasia. The tubulointerstitial damage as well as the glomerular collapse can also be seen in non-HIV primary collapsing GN, raising the question of common mechanisms to HIV and other non-identified viral agents related to the development of the disease. Although controversial, increasing evidence supports a direct effect of the virus on renal cells either as a result of exposure to viral proteins or direct renal parenchyma infection. The use of a HIV-1 transgenic mouse model has demonstrated a direct etiologic link between HIV-1 expression in kidney and the development of HIVAN with unique viral-host interactions, which depend at the same time on stimulating features of the virus and the individual nature of the host response. The infection of renal cells by HIV-1 could be detected by reverse transcription-polymerase chain reaction (RT-PCR) of gag RNA at a low level. Some studies using an HIV-1 transgenic mouse model have demonstrated that expression of HIV- 1 in the kidney is required for the development of HIVAN. The final common pathway in the development of HIV-associated nephropathy is likely to involve alterations in the patterns of gene expression of renal parenchyma cells by cytokines and growth factors, leading to interstitial fibrosis and enhanced glomerular matrix synthesis. The nature of the host response to viral infection is critical to the development of nephropathy.HLA-linked responses particular to a subset of blacks may explain some of the epidemiologic features of HIVAN. There may also be biological heterogeneity in the strains of HIV-1 that could account for a particular renotropic strain. HIV strains from different parts of the world may vary by as much as 15% at the level of nucleotide sequence. The infectivity of human immunodeficiency virus (HIV-1) in human glomerular cells has been evaluated by exposing homogeneous cultures of human glomerular capillary endothelial, mesangial and epithelial cells to HIV in vitro. The mechanism of access of HIV into glomerular endothelial and mesangial cells is unknown up to now; HIV is generally infectious for cells expressing the CD4 antigen in their cell membrane. Other modes of HIV entry into cells independent of the CD4 receptor are possible through mechanisms involving Fc-receptors or coinfection with other enveloped viruses such as HTLV-l. Our understanding of the pathogenesis of HIVAN has been aided by the development of a transgenic model. The curious fact that only 3 of 8 founded transgenic lines developed nephropathy emphasizes that the expression of viral gene products per se is not sufficient to produce nephropathy. Human renal epithelium does not express CD4 receptors and in vitro attempts to infect glomerular epithelial cells using laboratory strains of HIV-1 have proven fruitless. The striking morphologic and phenotypic similarities between HIVAN and collapsing idiopathic FSGS raise the question whether the altered podocyte gene expression in collapsing idiopathic FSGS may also be due to a viral infection. This hypothesis is further supported by de novo occurrence of collapsing idiopathic FSGS in immunosuppressed renal transplantation patients and by epidemiologic data. In conclusion, there are likely to be common mechanisms in the pathogenesis for collapsing idiopathic glomerulosclerosis and HIVAN. A primary injury of the podocyte leading to dysregulation of the cellular phenotype appears to mediate the glomerular tuft collapse in both conditions. Primary collapsing glomerulopathy recurs post-transplantation, raising the possibility of circulating factors implicated in the pathogenesis of visceral epithelial cell damage in steroid-resistant minimal change disease or recurrent FSGS. Recurrence of CG can occur hours after transplantation, suggesting that the plasma of CG patients contains one or more factors capable of inducing proteinuria due to the damage of the podocyte that results in the increase in glomerular permeability. In a rat model of CG developed by our group, the injection of serum from CG patients resulted in proteinuria, glomerular tuft retraction and podocyte damage at the ultrastructural level (visceral epithelial cell foot-process effacement). No ultrastructural or light microscopy abnormalities were seen in rats injected with serum from non-collapsing FSGS or healthy subjects. Based on the experience of our group, circulating factors play a dominant role in the pathogenesis of idiopathic CG.


Kangaroos display gazing and gaze alternations during an unsolvable problem task.
Domestication is generally assumed to have resulted in enhanced communication abilities between non-primate mammals and humans, although the number of species studied is very limited (e.g. cats, Felis catus; dogs, Canis familiaris; wolves, Canis lupus; goats, Capra hircus; horses, Equus caballus). In species without hands for pointing, gazing at humans when dealing with inaccessible food during an unsolvable task, and in particular gaze alternations between a human and the unsolvable task (considered forms of showing), are often interpreted as attempts at referential intentional communication. We report that kangaroos, marsupial mammals that have never been domesticated, actively gazed at an experimenter during an unsolvable problem task (10/11 kangaroos tested), thus challenging the notion that this behaviour results from domestication. Nine of the 10 kangaroos additionally showed gaze alternations between the unsolvable task and experimenter. We propose that the potential occurrence of these behaviours displayed towards humans has been underestimated, owing to a narrow focus on domestic animals, as well as a more general eutherian research bias.


Early changes in parameters of bone and mineral metabolism during therapy for hyper- and hypothyroidism.
The effects of thyroid hormones on various organs and metabolic systems have been the focus of intensive research. In this study we investigated the mechanisms of the changes in some parameters of bone and mineral metabolism before and during treatment of hyper- and hypothyroidism. Our study groups were as follows; 1) Untreated hyperthyroid patients (n= 38), 2) Hyperthyroid patients treated for three months (n=21), 3) Untreated hypothyroid patients (n=27), 4) Hypothyroid patients treated for three months (n= 20), and 5) Euthyroid control subjects (age, weight, sex and menopausal status matched) (n = 47). As expected, the mean serum calcium (Ca), phosphorus (P), alkaline phosphatase (ALP), and urinary Ca/creatinine and deoxypyridinoline (D-Pyr)/creatinine levels were higher in group-1 than in the control group. Serum PTH level was lower in group-1 than in group-5. However, after treatment for three months (group-2) we found that the serum and urinary levels of these parameters (except ALP) were not different than in the control group. Group-3 and group-4 did not show any differences in these parameters compared with group-5. Covariance analysis showed that urinary D-Pyr excretion had a positive, independent relationship to the serum free T3 level and age (P < 0.001 and P = 0.02, respectively). These results suggest that both bone formation and resorption markers increase in hyperthyroid patients, and with the treatment, particularly, in the period of first three months the bone resorption markers decrease rapidly. If the treatment is maintained the decrease slows, becoming more gradual. However, bone formation markers like ALP remain high in hyperthyroid patients during the treatment. In the light of this data, it is possible to conclude that osteoblastic activity lasts longer in hyperthyroidism. On the other hand, we demonstrated that these bone formation and resorption markers do not seem to be different in hypothyroid patients, even during the treatment, compared to the euthyroid controls.


Modulation of intracellular iron metabolism by iron chelation affects chromatin remodeling proteins and corresponding epigenetic modifications in breast cancer cells and increases their sensitivity to chemotherapeutic agents.
Iron plays a vital role in the normal functioning of cells via the regulation of essential cellular metabolic reactions, including several DNA and histone-modifying proteins. The metabolic status of iron and the regulation of epigenetic mechanisms are well-balanced and tightly controlled in normal cells; however, in cancer cells these processes are profoundly disturbed. Cancer-related abnormalities in iron metabolism have been corrected through the use of iron-chelating agents, which cause an inhibition of DNA synthesis, G₁-S phase arrest, an inhibition of epithelial-to-mesenchymal transition, and the activation of apoptosis. In the present study, we show that, in addition to these well-studied molecular mechanisms, the treatment of wild-type TP53 MCF-7 and mutant TP53 MDA-MB-231 human breast cancer cells with desferrioxamine (DFO), a model iron chelator, causes significant epigenetic alterations at the global and gene-specific levels. Specifically, DFO treatment decreased the protein levels of the histone H3 lysine 9 demethylase, Jumonji domain-containing protein 2A (JMJD2A), in the MCF-7 and MDA-MB-231 cells and down-regulated the levels of the histone H3 lysine 4 demethylase, lysine-specific demethylase 1 (LSD1), in the MDA-MB-231 cells. These changes were accompanied by alterations in corresponding metabolically sensitive histone marks. Additionally, we demonstrate that DFO treatment activates apoptotic programs in MCF-7 and MDA-MB-231 cancer cells and enhances their sensitivity to the chemotherapeutic agents, doxorubicin and cisplatin; however, the mechanisms underlying this activation differ. The induction of apoptosis in wild-type TP53 MCF-7 cells was p53-dependent, triggered mainly by the down-regulation of the JMJD2A histone demethylase, while in mutant TP53 MDA-MB-231 cells, the activation of the p53-independent apoptotic program was driven predominantly by the epigenetic up-regulation of p21.


Slant-gap plasmonic nanoantennas for optical chirality engineering and circular dichroism enhancement.
We present a new design of plasmonic nanoantenna with slant gap for optical chirality engineering. At resonance, the slant gap provides highly enhanced electric field parallel to external magnetic field with a phase delay of π/2, resulting in enhanced optical chirality. We show by numerical simulations that upon linearly polarized excitation our nanoantenna can generate near field with enhanced optical chirality which can be tuned by the slant angle and resonance condition. Our design allows chiral analysis with linearly polarized light and may find applications in circular dichroism analysis of chiral matter at surface.


Evaluation of a chemical risk assessment method of South Korea for chemicals classified as carcinogenic, mutagenic or reprotoxic (CMR).
Chemicals were used in various fields by the development of industry and science and technology. The Chemical Hazard Risk Management (CHARM) was developed to assess the risk of chemicals in South Korea. In this study, we were to evaluate the CHARM model developed for the effective management of workplace chemicals. We used 59 carcinogenic, mutagenic or reprotoxic (CMR) materials, which are both the work environment measurement result and the usage information among the manufacturer data. The CHARM model determines the risk to human health using the exposure level (based on working environment measurements or a combination of the quantity used and chemical physical properties (e.g., fugacity and volatility)), hazard (using occupational exposure limit (OEL) or Risk phrases (R-phrases)/Hazard statements (H-statements) from the Material Safety Data Sheet (MSDS)). The risk level was lower when using the results of the work environment measurement than when applying the chemical quantity and physical properties in the exposure level evaluation method. It was evaluated as grade 4 for the CMR material in the hazard class determination. The risk assessment method by R-phrases was evaluated more conservatively than the risk assessment method by OEL. And the risk assessment method by H-statements was evaluated more conservatively than the risk assessment method by R-phrases. The CHARM model was gradually conservatively assessed as it proceeded in the next step without quantitative information for individual workplaces. The CHARM is expected to help identify the risk if the hazards and exposure levels of chemicals were identified in individual workplaces. For CMR substances, although CHARM is highly evaluated for hazards, the risk is assessed to be low if exposure levels are assessed low. When evaluating the risk of highly hazardous chemicals such as CMR substances, we believe the model should be adapted to be more conservative and classify these as higher risk. Int J Occup Med Environ Health 2018;31(4):491-501.


Perceptions of Graduate Students at the University of São Paulo about Plagiarism Practices in Academic Works.
Our objective was to identify the understanding of theoretical aspects and the interpretation of practical situations that a sample of 3,623 graduate students (Population = 22,438) at the University of São Paulo (Brazil) have regarding academic plagiarism. The survey used an electronic questionnaire containing 30 multiple choice questions developed from the literature concerning the concept and definition of plagiarism, occurrence modality, types of plagiarism, reasons for occurrence, standards and preventive actions adopted. We identified that the fact of respondents agreeing or disagreeing with the theoretical-conceptual characteristics of plagiarism did not make a difference in their capacity of correctly assessing practical situations characterizing plagiarism. Moreover, the agreement or disagreement responses regarding the concepts of plagiarism were observed not to differ among the respondents who had been trained to use references and citations. However, the same respondents correctly interpret practical situations characterizing plagiarism. Therefore, this study suggests that there is a gap between theoretical and practical knowledge regarding plagiarism for graduate students. Although the technical training related to the correct use of research sources is an important prerequisite in the capacity-building process, it does not seem to be enough to prevent plagiarism practices.


Near-infrared emitting iridium(iii) complexes for mitochondrial imaging in living cells.
Biocompatible transition metal complexes dyes emitting in the near-infrared (NIR) region, are highly desirable in fluorescence imaging techniques. However, a high-performance mitochondria-specific labeling NIR probe with high photostability is still lacking. Herein we reported two NIR-emitting cationic iridium(iii) complexes [Ir(pbq-g)2(N^N)]+Cl- (pbq-g = phenylbenzo[g]-quinoline; N^N = 2-(1-benzyl-1H-pyrazol-3-yl) pyridine (Ir1) and 2-(1-(naphthalen-1-ylmethyl)-1H-pyrazol-3-yl) pyridine (Ir2)). These two novel Ir(iii) complexes with different N^N ligands exhibited similar NIR emission with λmax at 751 nm for Ir1 and 750 nm for Ir2 in PBS solution, with luminescence quantum yields of around 0.62 for Ir1 and 0.85 for Ir2. These two complexes showed high mitochondrial specificity, superior photostability, high resistance to the loss of the mitochondrial membrane potential and appreciable tolerance to environmental changes, allowing NIR imaging of mitochondrial morphological changes over long periods of time. These excellent photophysical and imaging properties made them promising NIR luminescent tags for applications in bioimaging.


Molecular pathology underlying the robustness of cancer stem cells.
Intratumoral heterogeneity is tightly associated with the failure of anticancer treatment modalities including conventional chemotherapy, radiation therapy, and molecularly targeted therapy. Such heterogeneity is generated in an evolutionary manner not only as a result of genetic alterations but also by the presence of cancer stem cells (CSCs). CSCs are proposed to exist at the top of a tumor cell hierarchy and are undifferentiated tumor cells that manifest enhanced tumorigenic and metastatic potential, self-renewal capacity, and therapeutic resistance. Properties that contribute to the robustness of CSCs include the abilities to withstand redox stress, to rapidly repair damaged DNA, to adapt to a hyperinflammatory or hyponutritious tumor microenvironment, and to expel anticancer drugs by the action of ATP-binding cassette transporters as well as plasticity with regard to the transition between dormant CSC and transit-amplifying progenitor cell phenotypes. In addition, CSCs manifest the phenomenon of metabolic reprogramming, which is essential for maintenance of their self-renewal potential and their ability to adapt to changes in the tumor microenvironment. Elucidation of the molecular underpinnings of these biological features of CSCs is key to the development of novel anticancer therapies. In this review, we highlight the pathological relevance of CSCs in terms of their hallmarks and identification, the properties of their niche-both in primary tumors and at potential sites of metastasis-and their resistance to oxidative stress dependent on system xc (-).


C'est vraiment compliqué: a case study on the delivery of maternal and child health and nutrition interventions in the conflict-affected regions of Mali.
Mali is currently in the midst of ongoing conflicts which involve jihadist groups, rebels, and the state. This conflict has primarily centered in the North of the country. Humanitarian actors delivering services in these geographies must navigate the complex environment created by conflict. This study aimed to understand how humanitarian actors make decisions around health service delivery within this context. The current case-study utilized a mixed methods approach and focused on Mopti, Mali's fifth administrative region and fourth largest in population. Latent content analysis was used to analyze interview transcripts guided by our research objectives and new concepts as they emerged. Indicators of coverage of health interventions in the area of maternal and child health and nutrition were compiled using Mali's National Evaluation Platform and are presented for the conflict and non-conflict regions. Development assistance estimates for Mali by year were obtained from the Developmental Assistance for Health Database compiled by the Institute for Health Metrics and Evaluation. Administrative data was compiled from the annual reports of Mali's Système Local d'Information Sanitaire (SLIS), Demographic and Health Surveys (DHS) and Multiple Indicator Cluster Surveys (MICS). Our data suggests that the reaction of the funding mechanisms to the conflict in Mali was a major barrier to timely delivery of health services to populations in need and the nature of the conflict is likely a key modifier of such reaction patterns. Concerns have been raised about the disconnect between the very high administrative capacity of large NGOs that control the work, and the consequent burden it puts on local NGOs. Population displacement and inaccurate estimates of needs made it difficult for organizations to plan program services. Moreover, actors delivering services to populations in need had to navigate an unpredictable context and numerous security threats. Our study highlights the need for a more flexible funding and management mechanism that can better respond to concerns and issues arising at a local level. As the conflict in Mali continues to worsen, there is an urgent need to improve service delivery to conflict-affected populations.


Alternative glycosylation controls endoplasmic reticulum dynamics and tubular extension in mammalian cells.
The endoplasmic reticulum (ER) is a central eukaryotic organelle with a tubular network made of hairpin proteins linked by hydrolysis of guanosine triphosphate nucleotides. Among posttranslational modifications initiated at the ER level, glycosylation is the most common reaction. However, our understanding of the impact of glycosylation on the ER structure remains unclear. Here, we show that exostosin-1 (EXT1) glycosyltransferase, an enzyme involved in N-glycosylation, is a key regulator of ER morphology and dynamics. We have integrated multiomics and superresolution imaging to characterize the broad effect of EXT1 inactivation, including the ER shape-dynamics-function relationships in mammalian cells. We have observed that inactivating EXT1 induces cell enlargement and enhances metabolic switches such as protein secretion. In particular, suppressing EXT1 in mouse thymocytes causes developmental dysfunctions associated with the ER network extension. Last, our data illuminate the physical and functional aspects of the ER proteome-glycome-lipidome structure axis, with implications in biotechnology and medicine.


[An imbalance between drive and guidance. A new model for the pathogenesis of schizophrenia].
We still do not know how genetic and environmental factors cause schizophrenia. The pathogenesis of this illness is unknown. To develop a pathogenetic model that has greater explanatory power than the existing hypotheses concerning schizophrenia. We searched the literature with the help of Medline (from 1966) using the search terms 'schizophrenia', 'basal ganglia', 'striatum' and 'cerebellum'. We also consulted recent manuals on schizophrenia, evolutionary psychiatry and neuroanatomy. The analysis showed that during the phylogenesis and ontogenesis of the brain two mechanisms, which are primarily motor-control mechanisms, are applied to the intentional level of functioning; one of these initiates and delivers power to intentions (the drive mechanism), whereas the other steers and guides intentions (the guidance mechanism). As a result of the repeated application of these two mechanisms an imbalance to the detriment of the drive mechanism in the end manifests itself as schizophrenia. The model clarifies the clinical and epidemiological findings and the course of the illness. The model provides a more comprehensive explanation for existing clinical and epidemiological data than do current alternatives. The model is compliable with the main prevailing views of psychiatrists on schizophrenia and it places the genesis of schizophrenia in an evolutionary perspective.


Step detection in single-molecule real time trajectories embedded in correlated noise.
Single-molecule real time trajectories are embedded in high noise. To extract kinetic or dynamic information of the molecules from these trajectories often requires idealization of the data in steps and dwells. One major premise behind the existing single-molecule data analysis algorithms is the gaussian 'white' noise, which displays no correlation in time and whose amplitude is independent on data sampling frequency. This so-called 'white' noise is widely assumed but its validity has not been critically evaluated. We show that correlated noise exists in single-molecule real time trajectories collected from optical tweezers. The assumption of white noise during analysis of these data can lead to serious over- or underestimation of the number of steps depending on the algorithms employed. We present a statistical method that quantitatively evaluates the structure of the underlying noise, takes the noise structure into account, and identifies steps and dwells in a single-molecule trajectory. Unlike existing data analysis algorithms, this method uses Generalized Least Squares (GLS) to detect steps and dwells. Under the GLS framework, the optimal number of steps is chosen using model selection criteria such as Bayesian Information Criterion (BIC). Comparison with existing step detection algorithms showed that this GLS method can detect step locations with highest accuracy in the presence of correlated noise. Because this method is automated, and directly works with high bandwidth data without pre-filtering or assumption of gaussian noise, it may be broadly useful for analysis of single-molecule real time trajectories.


Green tea polyphenol epigallocatechin-3-gallate and cranberry proanthocyanidins act in synergy with cathelicidin (LL-37) to reduce the LPS-induced inflammatory response in a three-dimensional co-culture model of gingival epithelial cells and fibroblasts.
The human antimicrobial peptide cathelicidin (LL-37) possesses anti-inflammatory properties that may contribute to attenuating the inflammatory process associated with chronic periodontitis. Plant polyphenols, including those from cranberry and green tea, have been reported to reduce inflammatory cytokine secretion by host cells. In the present study, we hypothesized that A-type cranberry proanthocyanidins (AC-PACs) and green tea epigallocatechin-3-gallate (EGCG) act in synergy with LL-37 to reduce the secretion of inflammatory mediators by oral mucosal cells. A three-dimensional (3D) co-culture model of gingival epithelial cells and fibroblasts treated with non-cytotoxic concentrations of AC-PACs (25 and 50 μg/ml), EGCG (1 and 5 μg/ml), and LL-37 (0.1 and 0.2 μM) individually and in combination (AC-PACs+LL-37 and EGCG+LL-37) were stimulated with Aggregatibacter actinomycetemcomitans lipopolysaccharide (LPS). Multiplex ELISA assays were used to quantify the secretion of 54 host factors, including chemokines, cytokines, growth factors, matrix metalloproteinases (MMPs), and tissue inhibitors of metalloproteinases (TIMPs). LL-37, AC-PACs, and EGCG, individually or in combination, had no effect on the regulation of MMP and TIMP secretion but inhibited the secretion of several cytokines. AC-PACs and LL-37 acted in synergy to reduce the secretion of CXC-chemokine ligand 1 (GRO-α), granulocyte colony-stimulating factor (G-CSF), and interleukin-6 (IL-6), and had an additive effect on reducing the secretion of interleukin-8 (IL-8), interferon-γ inducible protein 10 (IP-10), and monocyte chemoattractant protein-1 (MCP-1) in response to LPS stimulation. EGCG and LL-37 acted in synergy to reduce the secretion of GRO-α, G-CSF, IL-6, IL-8, and IP-10, and had an additive effect on MCP-1 secretion. The combination of LL-37 and natural polyphenols from cranberry and green tea acted in synergy to reduce the secretion of several cytokines by an LPS-stimulated 3D co-culture model of oral mucosal cells. Such combinations show promising results as potential adjunctive therapies for treating inflammatory periodontitis.


Theoretical aspects of Dynamic Nuclear Polarization in the solid state - the cross effect.
In recent years Dynamic Nuclear Polarization (DNP) signal enhancement techniques have become an important and integral part of modern NMR and MRI spectroscopy. The DNP mechanisms transferring polarization from unpaired electrons to the nuclei in the sample is accomplished by microwave (MW) irradiation. For solid samples a distinction is made between three main enhancement processes: Solid Effect (SE), Cross Effect (CE) and Thermal Mixing (TM) DNP. In a recent study we revisited the solid state SE-DNP mechanism at high magnetic fields, using a spin density operator description involving spin relaxation, for the case of an isolated electron spin interacting with neighboring nuclei. In this publication we extend this study by considering the hyper-polarization of nuclei in systems containing two interacting electrons. In these spin systems both processes SE-DNP and CE-DNP are simultaneously active. As previously, a quantum description taking into account spin relaxation is used to calculate the dynamics of spin systems consisting of interacting electron pairs coupled to (core) nuclei. Numerical simulations are used to demonstrate the dependence of the SE- and CE-DNP enhancements on the MW irradiation power and frequency, on electron, nuclear and cross relaxation mechanisms and on the spin interactions. The influence of the presence of many nuclei on the hyper-polarization of an individual core nucleus is examined, showing the similarities between the two DNP processes. These studies also indicate the advantages of the CE- over the SE-DNP processes, both driving the polarization of the bulk nuclei, via the nuclear dipole-dipole interactions.


Evaluation of stroke volume variation and pulse pressure variation as predictors of fluid responsiveness in patients undergoing protective one-lung ventilation.
In order to investigate whether the hemodynamic indices, including stroke volume variation (SVV) and pulse pressure variation (PPV) could predict fluid responsiveness in patients undergoing protective one-lung ventilation. 60 patients scheduled for a combined thoracoscopic and laparoscopic esophagectomy were enrolled and randomized into two groups. The patients in the protective group (Group P) were ventilated with a tidal volume of 6 mL/kg, an inspired oxygen fraction (FiO2) of 80%, and a positive end expiratory pressure (PEEP) of 5 cm H2O. Patients in the conventional group (Group C) were ventilated with a tidal volume of 8 mL/kg and a FiO2 of 100%. Dynamic variables were collected before and after fluid loading (7 mL/kg hydroxyethyl starch 6%, 0.4 mL/kg/min). Patients whose stroke volume index (SVI) increased by more than 15% were defined as responders. Data collected from 45 patients were finally analyzed. Twelve of 24 patients in Group P and 10 of 21 patients in Group C were responders. SVV and PPV significantly changed after the fluid loading. The receive operating characteristic (ROC) analysis showed that the thresholds for SVV and PPV to discriminate responders were 8.5% for each, with a sensitivity of 66.7% (SVV) and 75% (PPV) and a specificity of 50% (SVV) and 83.3% (PPV) in Group P. However, the thresholds for SVV and PPV were 8.5% and 7.5% with a sensitivity of 80% (SVV) and 90% (PPV) and a specificity of 70% (SVV) and 80% (PPV) in Group C. We found SVV and PPV could predict fluid responsiveness in protective one-lung ventilation, but the accuracy and ability of SVV and PPV were weak compared with the role they played in a conventional ventilation strategy.


Substance use among lesbian, gay, and bisexual clients entering substance abuse treatment: Comparisons to heterosexual clients.
This study evaluated whether sexual orientation-specific differences in substance use behaviors exist among adults entering substance abuse treatment. Admissions records (July 2007-December 2009) were examined for treatment programs in San Francisco, California receiving government funding. Lesbian, gay, and bisexual (LGB) persons (n = 1,441) were compared to heterosexual persons (n = 11,770) separately by sex, examining primary problem substance of abuse, route of administration, age of first use, and frequency of use prior to treatment. Regarding bisexual males, the only significant finding of note was greater prevalence of methamphetamine as the primary substance of abuse. When compared to heterosexual men, gay and bisexual men evidenced greater rates of primary problem methamphetamine use (44.5% and 21.8%, respectively, vs. 7.7%, adjusted odds ratios [ORs] 6.43 and 2.94), and there was lower primary heroin use among gay men (9.3% vs. 25.8%, OR 0.35). Among LGB individuals, race and ethnicity did not predict primary problem substance, except that among LGB men and women, a non-White race predicted cocaine use (OR 4.83 and 6.40, respectively), and among lesbian and bisexual women, Hispanic ethnicity predicted lower odds of primary cocaine use (OR 0.24). When compared to heterosexual men, gay men were more likely to smoke their primary problem substance (OR 1.61), first used this substance at an older age (M = 23.16 vs. M = 18.55, p < .001), and used this substance fewer days prior to treatment (M = 8.75 vs. M = 11.41, p < .001). There were no differences between heterosexual and lesbian or bisexual women. There were unique patterns of substance use for gay and bisexual men entering substance abuse treatment, but women did not evidence differences. Gay men evidenced unique factors that may reflect less severity of use when entering treatment including fewer days of use and a later age of initiation of their primary problem substances. The results underscore the importance of being sensitive to differences between gay, bisexual, and heterosexual males when considering substance use disorders. (PsycINFO Database Record


IMMUNE RESPONSE AND MITOSIS OF HUMAN PERIPHERAL BLOOD LYMPHOCYTES IN VITRO.
Phytohemagglutinin causes cultured lymphocytes to agglutinate, divide, and produce gamma-globulin. Most cells are transformed into large lymphocytes, some resembling plasmocytes. Actinomycin D stops gamma-globulin production after 2 hours. When specific antigens are added to lymphocytes from sensitized individuals, only some cells undergo morphological transformation, produce gamma-globulin, and divide. When cells or cell extracts from an unrelated individual are added to a culture, a similar reaction occurs.


The FANCM ortholog Fml1 promotes recombination at stalled replication forks and limits crossing over during DNA double-strand break repair.
The Fanconi anemia (FA) core complex promotes the tolerance/repair of DNA damage at stalled replication forks by catalyzing the monoubiquitination of FANCD2 and FANCI. Intriguingly, the core complex component FANCM also catalyzes branch migration of model Holliday junctions and replication forks in vitro. Here we have characterized the ortholog of FANCM in fission yeast Fml1 in order to understand the physiological significance of this activity. We show that Fml1 has at least two roles in homologous recombination-it promotes Rad51-dependent gene conversion at stalled/blocked replication forks and limits crossing over during mitotic double-strand break repair. In vitro Fml1 catalyzes both replication fork reversal and D loop disruption, indicating possible mechanisms by which it can fulfill its pro- and antirecombinogenic roles.


Interactions between the volume effects of hydroxyethyl starch 130/0.4 and Ringer´s acetate.
The turnover of Ringer´s solutions is greatly dependent on the physiological situation, such as the presence of dehydration or anaesthesia. The present study evaluates whether the kinetics is affected by previous infusion of colloid fluid. Ten male volunteers with a mean age of 22 years underwent three infusion experiments, on separate days and in random order. The experiments included 10 mL/kg of 6% hydroxyethyl starch 130/0.4 (Voluven™), 20 mL/kg of Ringer's acetate, and a combination of both, where Ringer´s was administered 75 minutes after the starch infusion ended. The kinetics of the volume expansion was analysed by non-linear least- squares regression, based on urinary excretion and serial measurement of blood haemoglobin concentration for up to 420 minutes. The mean volume of distribution of the starch was 3.12 L which agreed well with the plasma volume (3.14 L) estimated by anthropometry. The volume expansion following the infusion of starch showed monoexponential elimination kinetics with a half-life of two hours. Two interaction effects were found when Ringer´s acetate was infused after the starch. First, there was a higher tendency for Ringer´s acetate to distribute to a peripheral compartment at the expense of the plasma volume expansion. The translocated amount of Ringer´s was 70% higher when HES had been infused earlier. Second, the elimination half-life of Ringer´s acetate was five times longer when administered after the starch (88 versus 497 minutes, P<0.02). Starch promoted peripheral accumulation of the later infused Ringer´s acetate solution and markedly prolonged the elimination half-life. ClinicalTrials.gov: NCT01195025.


Memory During the Presumed Vegetative State: Implications for Patient Quality of Life.
A growing number of studies show that a significant proportion of patients, who meet the clinical criteria for the diagnosis of the vegetative state (VS), demonstrate evidence of covert awareness through successful performance of neuroimaging tasks. Despite these important advances, the day-to-day life experiences of any such patient remain unknown. This presents a major challenge for optimizing the patient's standard of care and quality of life (QoL). We describe a patient who, following emergence from a state of complete behavioral unresponsiveness and a clinical diagnosis of VS, reported rich memories of his experience during this time. This case demonstrates the potential for a sophisticated mental life enabled by preserved memory in a proportion of patients who, similarly, are thought to be unconscious. Therefore, it presents an important opportunity to examine the implications for patient QoL and standard of care, both during the period of presumed unconsciousness and after recovery.


An invariant surface patch on the TRIM5alpha PRYSPRY domain is required for retroviral restriction but dispensable for capsid binding.
TRIM5alpha is a retrovirus restriction factor in the host cell cytoplasm that blocks infection before provirus establishment. Restriction activity requires capsid (CA)-specific recognition by the PRYSPRY domain of TRIM5alpha. To better understand the restriction mechanism, nine charge-cluster-to-triple-alanine mutants in the TRIM5alpha PRYSPRY domain were assessed for CA-specific restriction activity. Five mutants distributed along the TRIM5alpha PRYSPRY primary sequence disrupted restriction activity against N-tropic murine leukemia virus and equine infectious anemia virus. Modeling of the TRIM5alpha PRYSPRY domain based on the crystal structures of PRYSPRY-19q13.4.1, GUSTAVUS, and TRIM21 identified a surface patch where disruptive mutants clustered. All mutants in this patch retained CA-binding activity, a reticular distribution in the cytoplasm, and steady-state protein levels comparable to those of the wild type. Residues in the essential patch are conserved in TRIM5alpha orthologues and in closely related paralogues. The same surface patch in the TRIM18 and TRIM20 PRYSPRY domains is the site of mutants causing Opitz syndrome and familial Mediterranean fever. These results indicate that, in addition to CA-specific binding, the PRYSPRY domain possesses a second function, possibly binding of a cofactor, that is essential for retroviral restriction activity by TRIM5alpha.